Published: Jan. 1, 2024
Language: Английский
International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 139823 - 139823
Published: Jan. 1, 2025
Language: Английский
Citations
1
Advanced Science, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 22, 2025
Abstract The relationship between patterns of RNA modifications and gastric cancer (GC) liver metastasis (GCLM) remains unclear. Here, by single‐cell sequencing, clinical sample analysis, mouse model studies, an abnormal increase in the expression acetyltransferase N‐acetyltransferase 10 (NAT10) metastatic GC cells is identified. NAT10‐mediated N4‐acetylcytidine modification CXCL2 KLF5 mRNA increases their stability. Then, secreted found to promote infiltration polarization M2‐like macrophages produce oncostatin M, which transcriptionally activates NAT10 via STAT3 signaling. In addition, organoid models confirm that promotes adhesion hepatocytes. Mechanistically, ITGαV, facilitating cell attachment Intriguingly, high NAT10/KLF5 axis associated with poor prognosis patients targeting this significantly reduces GCLM preclinical murine models. Collectively, these findings suggest significance developing targeted therapies for metastasis.
Language: Английский
Citations
1
European Heart Journal, Journal Year: 2024, Volume and Issue: unknown
Published: Oct. 25, 2024
Vascular smooth muscle cell (VSMC) phenotype switching is a pathological hallmark in various cardiovascular diseases. N4-acetylcytidine (ac4C) catalyzed by N-acetyltransferase 10 (NAT10) well conserved the enzymatic modification of ribonucleic acid (RNA). NAT10-mediated ac4C acetylation involved physiological and processes, including cardiac remodelling. However, biological functions underlying regulatory mechanisms mRNA modifications vascular diseases remain elusive.
Language: Английский
Citations
7
Oncogene, Journal Year: 2024, Volume and Issue: 43(15), P. 1077 - 1086
Published: Feb. 26, 2024
Language: Английский
Citations
5
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: March 27, 2024
ABSTRACT Human NAT10 acetylates the N4 position of cytidine in RNA, predominantly on rRNA and tRNA, to facilitate ribosome biogenesis protein translation. has been proposed as a therapeutic target cancers well aging-associated pathologies such Hutchinson-Gilford Progeria Syndrome (HGPS). The ∼120 kDa uses its acetyl-CoA-dependent acetyltransferase, ATP-dependent helicase, RNA binding domains concert mediate RNA-specific N4-cytidine acetylation. While biochemical activity is known, molecular basis for catalysis eukaryotic acetylation remains relatively undefined. To provide insights into by NAT10, we determined single particle cryo-EM structures Chaetomium thermophilum ( Ct NAT10) bound bisubstrate cytidine-CoA probe with without ADP. reveal that forms symmetrical heart-shaped dimer conserved functional surrounding acetyltransferase active sites harboring probe. Structure-based mutagenesis analysis mutants vitro supports catalytic role two site residues (His548 Tyr549 NAT10), basic patches, both proximal distal Yeast complementation analyses senescence assays human cells also implicates yeast thermoadaptation cellular senescence. Comparison structure lysine N-terminal enzymes reveals an unusually open suggesting these have evolutionarily tailored recognition cytidine-specific
Language: Английский
Citations
5
International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 140391 - 140391
Published: Jan. 1, 2025
Language: Английский
Citations
0
Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16
Published: Jan. 29, 2025
Succinylation represents an emerging class of post-translational modifications (PTMs), characterized by the enzymatic or non-enzymatic transfer a negatively charged four-carbon succinyl group to ϵ-amino lysine residues, mediated succinyl-coenzyme A. Recent studies have highlighted involvement succinylation in various diseases, particularly cancer progression. Sirtuin 5 (SIRT5), member sirtuin family, has been extensively studied for its robust desuccinylase activity, alongside deacetylase function. To date, only limited number SIRT5 substrates identified. These mediate diverse physiological processes such as glucose oxidation, fatty acid ammonia detoxification, reactive oxygen species scavenging, anti-apoptosis, and inflammatory responses. The regulation these activities can occur through either same activity acting on different distinct targeting substrate. Aberrant expression closely linked tumorigenesis disease progression; however, role remains controversial. exhibits dual functionalities: it promote tumor proliferation, metastasis, drug resistance, metabolic reprogramming, thereby oncogene; conversely, also inhibit cell growth induce apoptosis, functioning suppressor gene. This review aims provide comprehensive overview current research status SIRT5. We discuss structural characteristics regulatory mechanisms, compare functions with other family members, elucidate mechanisms regulating activity. Specifically, we focus modification progression, highlighting how desuccinylation modulates development delineating underlying involved.
Language: Английский
Citations
0
EJNMMI Radiopharmacy and Chemistry, Journal Year: 2025, Volume and Issue: 10(1)
Published: Jan. 31, 2025
Language: Английский
Citations
0
Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)
Published: Feb. 4, 2025
Abstract Background Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and treatment options for advanced CRC are limited. The regulatory mechanisms aberrant NAT10-mediated N4-acetylcytidine (ac4C) modifications in progression remains poorly understood. Consequently, an integrated transcriptomic analysis necessary to fully elucidate role ac4C progression. Methods NAT10 expression levels were analyzed samples compared with those corresponding normal tissues. potential investigated using RNA sequencing, immunoprecipitation acetylated sequencing. Additional vivo vitro experiments, including CCK-8 assays, colony formation mouse xenograft models, conducted explore biological modifications. We also evaluated optimized a strategy targeting NAT10. Results found that highly expressed plays pro-oncogenic role. knockdown led PI3K-AKT pathway inactivation, thereby inhibiting However, inhibitor Remodelin induced only limited reversible growth arrest cells. Further epigenetic revealed enhances stability ERRFI1 mRNA by binding its coding sequence region ac4C-dependent manner. decreased expression, which subsequently activated EGFR counteracted inhibitory effects on CRC. Based these findings, we demonstrated dual inhibition EGFR-specific monoclonal antibody cetuximab resulted improved therapeutic efficacy either drug alone. Moreover, observed 5-Fluorouracil promoted interaction between UBR5, increased ubiquitin-mediated degradation NAT10, downregulation reactivation. Triple therapy Remodelin, cetuximab, enhanced tumor regression models wild-type KRAS, NRAS BRAF. Conclusions Our study elucidated mechanism underlying 5-Fu-induced downregulation, revealing destabilizes through modifications, resulting A triple regimen 5-Fu showed as
Language: Английский
Citations
0
Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(15)
Published: April 7, 2025
Increased differentiation or activity of osteoclasts is the key pathogenic factor postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, a novel posttranscriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with monocytes and low bone mass PMOP. The specific knockout Nat10 remodelin, inhibitor, alleviates ovariectomized (OVX)-induced loss downregulating differentiation. Mechanistically, epitranscriptomic analyses reveal nuclear activated T cells cytoplasmic 1 (Nfatc1) downstream target during Subsequently, translatomic results demonstrate enhances translation efficiency (TE) Nfatc1, thereby inducing Nfatc1 expression consequent maturation. Cumulatively, these findings promotive role from field RNA modifications suggest can be epigenetic therapy for preventing
Language: Английский
Citations
0